#2021BSQ-NOV Q31
These are more clearly seen in type I DM.
In type 2 DM, vascular and tubulointerstitial changes predominate.

1. changes in glomerular hemodynamics
   1. DM -> somehow ↑ RAAS activity -> increased GFR -> In early stages of DM: Glomerular hyperfiltration.
   2. Glomerular HYPERFILTRATION is a recognized phenomenon in early diabetes.
   3. Hyperfiltration is associated with increased risk of progression of kidney function decline.
   4. Also, renal autoregulation of blood flow may be impaired - exposing the kidney to effects of hypertension. => increased GFR
2. Oxidative stress and inlammation
   1. DM -> Advanced Glycation End products (AGE) -> inflammation
3. Interstitial fibrosis and tubular atrophy.
   1. DM -> Hyperglycaemia -> ↑ activity of hexosamine pathway +↑ RAAS acvitity -> ↑ TGF-Beta production -> fibrosis and atrophy

Glomerular changes

Mesangial proliferation -> further proliferation + matrix deposition -> PAS positive kimmelstiel-Wilson bodies.

1. Diffuse basement membrane thickening along it's entire length
2. Diffuse mesangial sclerosis <- diffuse increase of mesangial cells and matrix.
3. Nodular glomerular sclerosis <- a pattern of sclerosis with nodules of matrix at the periphery of the glomerulus. AKA Kimmelstiel Wilson nodules. <- Pathognomonic of DM (almost)
   These changes are present in all patients with renal impairment in T1 DM.

Chronological sequence of changes

1. Glomerular basement membrane thickening is the first to be seen.
2. Thickening of the tubular basement membrane parallels GBM thickening.
3. Mesangial proliferation and sclerosis is seen later.

[!INFO]
This 'neat' sequence is best observed in type 1 DM. It's more complicated in Type 2

Non glomerular changes

• Efferent and afferent arteriolar hyalinosis - Deposition of plasma proteins (complement, immunoglobulins and fibrinogen) replace the smooth muscle cells of arteriole.

[!INFO]

Glomerulus from a type 1 diabetic (T1DM) patient with diffuse (long thick arrow) and nodular (short thick arrow) mesangial expansion and afferent (double thin arrows) and efferent (single thin arrow) arteriolar hyalinosis. Source

[!INFO] Is an autoimmume, T cell infiltrative disease.
#2021BSQ-NOV Q32

• Autoimmunity -> TSH-Receptor antibodies (thyrotropin receptor or TRAb) stimulate thyroid gland to make thyroid hormones. -> diffuse, non tender, goiter. (MCQ Point: TSH receptor inhibiting antibodies are also formed)
• Histology: Diffuse, hyperplasia and hypertrophy; follicular cells become tall and columnar with crowding and formation of papillae with no neovascularization. T cell infiltrates are present within thyroid.
• Graves eye disease is a prominent feature. Occurs because of T cell infiltrations;
  • Volume of retro-orbital tissue is increased by 1) T cell infiltration, 2) Inflammatory oedema, 3) Increased extracellular matrix deposition, 4) increased adipocytes.
• Orbitopathy and pretibial myxoedema are not related to thyroxine levels. Pretibial myxoedema is caused by deposition of glycosaminoglycans and T cell infiltration.

#2021BSQ-NOV Q31

Leukemoid reaction refers to a white blood cell (WBC) count >50,000/microL from causes other than leukemia. (Usually severe reaction to an infection).

The majority of cells are mature neutrophils, but often accompanied by a prominent left shift.

[!INFO] Left shift
"Left shift" : ill defined term meaning increased band forms, myelocytes and metamyelocytes. -> indicates infection, sepsis of chronic myeloid leukemia.
Myelocytes are neutrophil precursors seen mainly in bone marrow. Metamyelocytes are their descendants, and can be seen in the blood.
Greek "meta" means 'after'.
Band forms are immature neutrophils whose nucleus hasn't yet become segmented and have a C or S shape.

Some Causes:

• Infections: Tuberculosis infection, Clostridium difficile infection, pertussis
• Asplenia / hyposplenia
• Medications: myeloid cytokines and all-trans retinoic acid.

Clues for cause or neutrophilia:

1. Toxic granules present or Dohle bodies -> Infection / inflammation
2. Left shift -> infection or Chronic myeloid leukemia.
3. Significant number of myeloid blasts -> Acute myeloid leukemia

Spurious neutrophilia / false neurophilia / pseudo neutrophilia:
interferrenace with the particle counter can case false neutrophelia in

• Platelet clumping
• Cryoglobulinaemia

Cellular adaptations

#2021BSQ-NOV Q34

Hyperplasia and hypertrophy

Important points:

• Hyperplasia occurs in cells that retain the ability to divide (eg. Smooth muscle of uterus). Hypertrophy occurs in cells that cannot divide (eg. Cardiac and Skeletal muscle)
• Both hyperplasia and hypertrophy can occur simultaneously. (eg Gravid uterus)
• Both can be physiological or pathological. (LVH in hypertension)
• Stimuli for hypertrophy can be mechanism or chemical (signalling molecules).
• If stress exceed adaptive capabilities of cell, cell injury results.
  • Hypertrophy has limits; when a particular limit of adaptive hypertrophy is reached, degenerative changes occur in the contractile unites of muscle. This is seen in decompensation of heart failure. The degenerative changes results in ventricular dilation.
• Hyperplasia: stimulated by growth factors. Can occur simulatenously with hypertrophy.
• There are two types of physiologic hyperplasia
  • Hormonal -> in response to hormones
  • Compensatory -> Remaining liver cells begin to divide after liver resection due to paracrine peptide signals.
• Pathologic hyperplasia: caused by abnormal hormone production: eg endometrial hyperplasia.
• Pathologi hyperplasia is distinguised from cancer by the preserved sensitivity of cells to external growth factors. i.e in pathologic hyperplasia, if the growth factor is removed, hyperplasia stops. (but not in cancer)

Atrophy

Causes:

• Decreased work load (cells aren't needed)
• Loss off innervation (cells think they aren't needed)
• Inadequate nutrition
• Loss of blood supply
• Aging (senile atrophy)

[!INFO] Definition of atrophy
In atrophy, a shell shrinks to a smaller size with reduced function so that it can survive under the new (less conducive) growth conditions imposed by factors listed above.
Atrophic cells are not dead.
Cellular mechanisms:

• Decreased protein synthesis
• Proteolysis - ubiquitin-proteasome pathway which may also be involved in cancer cachexia
• Increased autophagy.

Metaplasia

Reprogramming of stem cells to differentiate into a cell type that is more suitable to cope with the new stresses than the original cell type at that location.
I.e results in replacement of one type of mature cell with another type of mature cell.
It is a reversible change;
Example: Squamous metaplasia of respiratory epithelium in smokers.
Vitamin A is essential for normal epithelial differentiation.

Pathology of cancers

Anaplasia

Anaplasia: "backward formation" - loss of structural and functional differentiation of cells. A hallmark of malignancy

[!INFO] Dedifferentiation Vs. Lack of differentiation
There may be some technical difference between dedifferentiation and inability to differentiate at all (as seen in cancers of stem cells)
See Robbins (Page 165).

Pathologic features of anaplastic cells:

• Anaplastic cells show pleomorphism: variation in size and shape.
• Extremely hyperchromatic nuclei.
• Large nuclei with high nuclear to cytoplasmic ratio.
• Bizzare nuclear shapes
• Numerous and atypical mitoses.

Dysplasia

Dysplasia:

• "Anarchy or normal cellular order" ->
• Mainly seen in epithelial lesions.
• There is
  • Pleomorphism with large, hyperchromatic nuclei.
  • Loss of cellular uniformity
  • loss of cell orientation
  • Increased mitotic count with mitoses in unusual areas (i.e away from basement membrane)
• Dysplasia generally precedes malignant transformation at that site.
• However, mild to moderate dysplasia can spotaneously regress as well.
• Therefore, dysplasia is NOT synonymous with cancer.
• Dysplasia involving all layers of the epithelium is called carcinoma in situ.

Infectious causes of cancer

==From Wikipedia==

• 
• Cryoglubulins can cause a systemic small to medium vessel vasculitis triggered by cryoglobulin containing immune complexes.
• Type 1 - caused by cryoprecipitable monoclonal immunoglobulins.

Gatric cancer can be

• Gastrooesophageal
• Proximal
• Distal
  Distal cancer incidence as reduced greatly but proximal and GE cancer incidence has increased.

H. pylori and gastric cancer

H pylori infection is associated with several types of gastric cancer.
Treatment of H pylori infection reduces cancer risk.
The exact mechanism is not known but there are several theories.

• H pylori may increase [[2022 May Basic Sciences#Gastric cancer|Gastrin]] secretion as above.
• H pylori can cause chronic gastritis leading to metaplasia.

Types of cancer associated with H. pylori:

• Gatric adenocarcinoma (both diffuse and intestinal types)

(AKA TNF-alpha, AKA TNF-α, aka cachexin)

1. mitochondrial or intrinsic pathway => promoted by DNA damange and accumulation of misfolded proteins. Pro apoptotic proteins leak out of the mitrochondria; This pathway is inhibited when the cell receives growth signals.

Endothelial cell contraction occurs rapidly after binding of histamine, bradykinin, leukotrienes, and many other mediators to specific receptors, and is usually short-lived (15 to 30 minutes). A slower and more prolonged retraction of endothelial cells, resulting from changes in the cytoskeleton, may be induced by cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1).

1. TNF
   TNF and IL-1 : the main role of TNF and IL-1 is in endothelial cell activation which causes increased vascular permeability and increased expression of adhesion molecules to facilitate phagocyte (neutrohil) migration and to enhance production of chemokines and other cytokines.

Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.

[!INFO] Hurthle cells are seen in non malignant conditions as well
Hurthle cells are clasically seen in

• Hashimoto thyroiditis
• multinodular hypoplasia
• lymphocytic thyroidis
• Source

#2021BSQ-NOV Q33

• Molecules whose concentration Incr. or Decr. by 25% during inflammation.
• Plasma levels are mainly controlled by rate of hepatic production.
• Hepatic production is regulated by cytokines - IL-6, IL-1 beta, TNF-alpha and interferron Gamma secreted by macrophages during inflammation.

"For F*cks Sake, Protect Harry's Ass Hole " - +ve acute phase reactancts.